Buprenorphine Use Trends Following Removal of Prior Authorization Policies for the Treatment of Opioid Use Disorder in 2 State Medicaid Programs.

Importance: State Medicaid programs have implemented initiatives to expand treatment coverage for opioid use disorder (OUD); however, some Medicaid programs still require prior authorizations (PAs) for filling buprenorphine prescriptions. Objective: To evaluate the changes in buprenorphine use for OUD among Medicaid enrollees in states that completely removed buprenorphine PA requirements. Design Setting and Participants: This retrospective cross-sectional study analyzed the immediate and trend changes on buprenorphine use during 2013 to 2020 associated with removal of PA requirements using a controlled interrupted time series analysis to account for autocorrelation. Data were collected from Medicaid State Drug Utilization Data for 2 states (California and Illinois) that completely removed a buprenorphine PA during the study period, and buprenorphine prescriptions for OUD treatment were identified among Medicaid enrollees. Main Outcomes and Measures: Quarterly total number of buprenorphine prescriptions for each state was calculated, and stratification analyses were conducted by dosage form (films and tablets). Results: Among the 2 state Medicaid programs (California and Illinois) that removed buprenorphine PAs, there was a total of 702 643 and 415 115 eligible buprenorphine prescription claims, respectively. After removing PA requirements for buprenorphine, there was an immediate increase that was not statistically significant (rate ratio [RR], 1.11; 95% CI, 0.76-1.61) in the number of all buprenorphine prescriptions in California and a statistically significant increase (RR, 6.99; 95% CI, 4.67-10.47) in the number of all buprenorphine prescriptions in Illinois relative to the change in the control states (Alabama, Florida, Idaho, Kansas, Mississippi, Nevada, South Dakota, and Wyoming). Additionally, there was a statistically significant decreasing trend in the number of all buprenorphine prescriptions in California (RR, 0.88; 95% CI, 0.82-0.94) and a statistically significant increasing trend in Illinois (RR, 1.11; 95% CI, 1.05-1.19) relative to the trend in control states. Conclusions and Relevance: In this cross-sectional study, removal of buprenorphine PA requirements was associated with a statistically significant increase in the number of buprenorphine prescription fills among Medicaid populations in 1 of the 2 included states.

Characteristics of academic medicine change agents as revealed by 4th-year medical students' reflections-on-practice.

PROBLEM: At present, formal training in adult learning principles, educational theories, and educational methods is not a core objective of most medical school curricula. As academic medical centers aim to develop the next generation of medical educators, students must be provided an opportunity to learn educational principles, engage in supervised teaching activities, and develop experiences in academic medicine to foster interest early in their development as educators. INTERVENTION: We developed a longitudinal medical education elective for fourth-year medical students, which was comprised of attending five seminars, leading 15 teaching sessions, formulating a medical education project, and writing a reflective essay. The seminars covered the history of medical education in the USA, adult learning theory and teaching principles, use of various teaching strategies and formats, construction and organization of curricula, effective models of evaluation and feedback provision, and principles of educational research. CONTEXT: This exploratory quasi-experiment incorporated a concurrent mixed methods data collection approach via pre- and post-seminar surveys and narrative reflection essay document analyses. IMPACT: Learners revealed favorable changes in their self-efficacy and self-perceived knowledge and attitudes towards medical education. A qualitative analysis of the reflective essays revealed five thematic categories (learning impacts, medical educator growth, leadership growth, medical school reflections, and future professional plans) and thirteen sub-categories. Students found many opportunities to implement high-quality educational projects, expressed commitment to pursuing teaching careers, and felt better equipped to assume a leadership role as change agents in academic medicine. LESSONS LEARNED: Findings are likely relevant to critical stakeholders who advocate for the inclusion of formal educational skills training into medical education curricula.

Too Hot to Handle: A Case of Fever of Unknown Origin.

Fever of unknown origin (FUO) is defined as a fever higher than 38.3ºC for at least three weeks. It remains a difficult diagnostic challenge and it carries well over 200 differential diagnoses, including infectious, rheumatologic and malignant etiologies. A methodological approach with clinical deductive reasoning and value-based investigative work-up can establish the diagnosis. This case is about a 76-year-old male with a past medical history of atrial fibrillation, bladder cancer treated with chemotherapy (now in remission) and hydronephrosis with recent ureteropelvic junction stent placement. He presented to the emergency department (ED) for worsening shortness of breath (SOB), weakness, and fevers. His initial workup was notable for a urinary tract infection which was treated with ceftriaxone. However, there was only a limited improvement in the fever. Diagnostic imaging was negative on initial review. He was evaluated by consultants of different specialities including infectious disease, rheumatology, and hematology. Ultimately, the decision was made to discharge the patient home on steroids with further outpatient workup. He returned four weeks later with worsening fever and was found to have new-onset mediastinal lymphadenopathy. A biopsy of an inguinal lymph node was obtained which showed high grade-B cell lymphoma. The patient was continued on prednisone and started on chemotherapeutic agents which included vincristine, rituximab and cyclophosphamide. Shortly after starting treatment, the patient and family elected for hospice. This case demonstrates the importance of continuously questioning the diagnosis at hand and of keeping an open mind when evaluating a patient with FUO.

Trends in Use of Prescription Nonsteroidal Anti-inflammatory Medications Before vs After Implementation of a Florida Law Restricting Opioid Prescribing for Acute Pain.

Importance: Previous research has shown an immediate reduction in new opioid users and use after implementation of the opioid supply restriction laws. Assessment of the association between opioid restrictions and alternative treatment options, such as nonsteroidal anti-inflammatory drugs (NSAIDs), is needed to evaluate potential unintended consequences for patients requiring analgesia. Objective: To evaluate the association between an opioid restriction law in Florida and use of prescription NSAIDs. Design, Setting, and Participants: This quality improvement study used interrupted time series analyses accounting for autocorrelation to estimate immediate and trend changes in the prescribing and use of prescription NSAIDs in Florida before and after implementation of a state law limiting opioid prescriptions to a 3-day supply. Participants were enrollees in a single private health plan of a large university and health system employer in Florida from January 2015 to June 2019. Exposures: Prescriptions for NSAIDs, ascertained from pharmacy claims data. Main Outcomes and Measures: The following outcomes were calculated monthly per 1000 plan enrollees: (1) number of NSAID users; (2) mean days' supply of NSAIDs per prescription; and (3) mean number of NSAID prescriptions. Individuals were classified as NSAID users if they had at least 1 NSAID prescription in a given month. Analysis was stratified by route of NSAID administration (oral or nonoral). Results: Among 46 783 NSAID users with 79 089 NSAID prescriptions during the study period, the median age was 47 years (interquartile range, 35-57 years). After implementation of the opioid restriction law, the number of NSAID users immediately increased, but the difference was not significant (change, 0.82 per 1000 patients; 95% CI, -0.67 to 2.30 per 1000 patients). No significant change in the days' supply of oral NSAID users occurred (change, 0.21 days per prescription; 95% CI, -1.66 to 2.08 days per prescription). Before implementation of the law, there was a nonsignificant decreasing trend in NSAID prescriptions (rate of change, -0.03 per month per 1000 enrollees; 95% CI, -0.13 to 0.07 per month per 1000 enrollees; after implementation, there was a nonsignificant increase in the number of oral and nonoral NSAID prescriptions (change, 1.49 per 1000 enrollees; 95% CI, -3.38 to 6.37 per 1000 enrollees). Conclusions and Relevance: In this quality improvement study, prescribing and use of prescription NSAIDs did not increase after implementation of a law restricting opioid analgesic prescriptions in Florida. These findings suggest possible greater use of over-the-counter NSAIDs after implementation of the law, but further research is needed to evaluate changes in the use of nonopioid analgesics and alternative pain therapies.

Changes in Quantity of Opioids Dispensed following Florida's Restriction Law for Acute Pain Prescriptions.

OBJECTIVE: To assess the impact of Florida's 3-day opioid prescription supply law, effective July 2018, on opioids dispensed for acute pain patients. METHODS: Pharmacy claims from a health plan serving a large Florida employer from January 2015 through March 2019 were analyzed. We used an interrupted time series study design accounting for autocorrelation of trends before and after policy change. Acute pain patients met inclusion criteria if they had not received any opioid containing medications in the past 180 days. Patients could contribute to additional new use time if subsequent opioid claims occurred ≥180 days since the previous claim. Outcomes included mean number of units dispensed of the initial opioid prescription, mean morphine milligram equivalents (MMEs) per day of initial prescription by month, and mean total MMEs per initial prescription by month. RESULTS: A total of 8,375 enrollees had 10,583 unique opioid starts in the given timeframe. Following the policy, there was an immediate significant decrease in the units dispensed per prescription of 4.9 (95% confidence interval [CI] -8.95, -.82 units). Additionally, there was a significant immediate reduction in total MMEs dispensed per prescription of 25.6 (95% CI -44.76, -6.44 MMEs). CONCLUSIONS: Among a group of privately-insured plan enrollees in Florida, and as a result of the law, there were significant decreases in the number of units dispensed, and total MMEs of opioid prescriptions. The immediate reduction in new opioid utilization following policy implementation suggests effective policy; however, impacts on chronic pain patients were not assessed.

Necrotic Ulcers Secondary to Apomorphine Infusion.

Background: Apomorphine is a potent dopamine agonist used in the treatment of advanced and fluctuating Parkinson's Disease. However the need for its subcutaneous infusion can lead to skin reactions. Phenomenology Shown: We illustrate necrotic ulcers at infusion sites as a rare event during continuous subcutaneous apomorphine infusion. Educational value: This case demonstrates the rare adverse event of necrotic ulcers in a patient with long term apomorphine infusion.

Chronic Opioid Therapy: A Scoping Literature Review on Evolving Clinical and Scientific Definitions.

The management of chronic noncancer pain (CNCP) with chronic opioid therapy (COT) is controversial. There is a lack of consensus on how COT is defined resulting in unclear clinical guidance. This scoping review identifies and evaluates evolving COT definitions throughout the published clinical and scientific literature. Databases searched included PubMed, Embase, and Web of Science. A total of 227 studies were identified from 8,866 studies published between January 2000 and July 2019. COT definitions were classified by pain population of application and specific dosage/duration definition parameters, with results reported according to PRISMA-ScR. Approximately half of studies defined COT as "days' supply duration >90 days" and 9.3% defined as ">120 days' supply," with other days' supply cut-off points (>30, >60, or >70) each appearing in <5% of total studies. COT was defined by number of prescriptions in 63 studies, with 16.3% and 11.0% using number of initiations or refills, respectively. Few studies explicitly distinguished acute treatment and COT. Episode duration/dosage criteria was used in 90 studies, with 7.5% by Morphine Milligram Equivalents + days' supply and 32.2% by other "episode" combination definitions. COT definitions were applied in musculoskeletal CNCP (60.8%) most often, and typically in adults aged 18 to 64 (69.6%). The usage of ">90 days' supply" COT definitions increased from 3.2 publications/year before 2016 to 20.7 publications/year after 2016. An increasing proportion of studies define COT as ">90 days' supply." The most recent literature trends toward shorter duration criteria, suggesting that contemporary COT definitions are increasingly conservative. PERSPECTIVE: This study summarized the most common, current definition criteria for chronic opioid therapy (COT) and recommends adoption of consistent definition criteria to be utilized in practice and research. The most recent literature trends toward shorter duration criteria overall, suggesting that COT definition criteria are increasingly stringent.

Loss of cytosolic Mg2+ binding sites in the Thermotoga maritima CorA Mg2+ channel is not sufficient for channel opening.

The CorA Mg2+ channel is a homopentamer with five-fold symmetry. Each monomer consists of a large cytoplasmic domain and two transmembrane helices connected via a short periplasmic loop. In the Thermotoga maritima CorA crystal structure, a Mg2+ is bound between D89 of one monomer and D253 of the adjacent monomer (M1 binding site). Release of Mg2+ from these sites has been hypothesized to cause opening of the channel. We generated mutants to disrupt Mg2+ interaction with the M1 site. Crystal structures of the D89K/D253K and D89R/D253R mutants, determined to 3.05 and 3.3 Å, respectively, showed no significant structural differences with the wild type structure despite absence of Mg2+ at the M1 sites. Both mutants still appear to be in the closed state. All three mutant CorA proteins exhibited transport of 63Ni2+, indicating functionality. Thus, absence of Mg2+ from the M1 sites neither causes channel opening nor prevents function. We also provide evidence that the T. maritima CorA is a Mg2+ channel and not a Co2+ channel.

Dissociation between urate and blood pressure in mice and in people with early Parkinson's disease.

BACKGROUND: Epidemiological, laboratory and clinical studies have established an association between elevated urate and high blood pressure (BP). However, the inference of causality remains controversial. A naturally occurring antioxidant, urate may also be neuroprotective, and urate-elevating treatment with its precursor inosine is currently under clinical development as a potential disease-modifying strategy for Parkinson's disease (PD). METHODS: Our study takes advantage of a recently completed phase II trial evaluating oral inosine in de novo non-disabling early PD with no major cardiovascular and nephrological conditions, and of three lines of genetically engineered mice: urate oxidase (UOx) global knockout (gKO), conditional KO (cKO), and transgenic (Tg) mice with markedly elevated, mildly elevated, and substantially reduced serum urate, respectively, to systematically investigate effects of urate-modifying manipulation on BP. FINDINGS: Among clinical trial participants, change in serum urate but not changes in systolic, diastolic and orthostatic BP differed by treatment group. There was no positive correlation between urate elevations and changes in systolic, diastolic and orthostatic BP ((p = .05 (in inverse direction), 0.30 and 0.63, respectively)). Between UOx gKO, cKO, or Tg mice and their respective wildtype littermates there were no significant differences in systolic or diastolic BP or in their responses to BP-regulating interventions. INTERPRETATION: Our complementary preclinical and human studies of urate modulation in animal models and in generally healthy early PD do not support a hypertensive effect of urate elevation or an association between urate and BP. FUND: U.S. Department of Defense, RJG Foundation, Michael J. Fox Foundation LEAPS program, National Institutes of Health, American Federation for Aging Research, Parkinson's Disease Foundation Advancing Parkinson's Therapies initiative.

Evaluation of a complex intervention (Engager) for prisoners with common mental health problems, near to and after release: study protocol for a randomised controlled trial.

INTRODUCTION: The 'Engager' programme is a 'through-the-gate' intervention designed to support prisoners with common mental health problems as they transition from prison back into the community. The trial will evaluate the clinical and cost-effectiveness of the Engager intervention. METHODS AND ANALYSIS: The study is a parallel two-group randomised controlled trial with 1:1 individual allocation to either: (a) the Engager intervention plus standard care (intervention group) or (b) standard care alone (control group) across two investigation centres (South West and North West of England). Two hundred and eighty prisoners meeting eligibility criteria will take part. Engager is a person-centred complex intervention delivered by practitioners and aimed at addressing offenders' mental health and social care needs. It comprises one-to-one support for participants prior to release from prison and for up to 20 weeks postrelease. The primary outcome is change in psychological distress measured by the Clinical Outcomes in Routine Evaluation-Outcome Measure at 6 months postrelease. Secondary outcomes include: assessment of subjective met/unmet need, drug and alcohol use, health-related quality of life and well-being-related quality of life measured at 3, 6 and 12 months postrelease; change in objective social domains, drug and alcohol dependence, service utilisation and perceived helpfulness of services and change in psychological constructs related to desistence at 6 and 12 months postrelease; and recidivism at 12 months postrelease. A process evaluation will assess fidelity of intervention delivery, test hypothesised mechanisms of action and look for unintended consequences. An economic evaluation will estimate the cost-effectiveness. ETHICS AND DISSEMINATION: This study has been approved by the Wales Research Ethics Committee 3 (ref: 15/WA/0314) and the National Offender Management Service (ref: 2015-283). Findings will be disseminated to commissioners, clinicians and service users via papers and presentations. TRIAL REGISTRATION NUMBER: ISRCTN11707331; Pre-results.

Vector-free intracellular delivery by reversible permeabilization.

Despite advances in intracellular delivery technologies, efficient methods are still required that are vector-free, can address a wide range of cargo types and can be applied to cells that are difficult to transfect whilst maintaining cell viability. We have developed a novel vector-free method that uses reversible permeabilization to achieve rapid intracellular delivery of cargos with varying composition, properties and size. A permeabilizing delivery solution was developed that contains a low level of ethanol as the permeabilizing agent. Reversal of cell permeabilization is achieved by temporally and volumetrically controlling the contact of the target cells with this solution. Cells are seeded in conventional multi-well plates. Following removal of the supernatant, the cargo is mixed with the delivery solution and applied directly to the cells using an atomizer. After a short incubation period, permeabilization is halted by incubating the cells in a phosphate buffer saline solution that dilutes the ethanol and is non-toxic to the permeabilized cells. Normal culture medium is then added. The procedure lasts less than 5 min. With this method, proteins, mRNA, plasmid DNA and other molecules have been delivered to a variety of cell types, including primary cells, with low toxicity and cargo functionality has been confirmed in proof-of-principle studies. Co-delivery of different cargo types has also been demonstrated. Importantly, delivery occurs by diffusion directly into the cytoplasm in an endocytic-independent manner. Unlike some other vector-free methods, adherent cells are addressed in situ without the need for detachment from their substratum. The method has also been adapted to address suspension cells. This delivery method is gentle yet highly reproducible, compatible with high throughput and automated cell-based assays and has the potential to enable a broad range of research, drug discovery and clinical applications.

Open Targets: a platform for therapeutic target identification and validation.

We have designed and developed a data integration and visualization platform that provides evidence about the association of known and potential drug targets with diseases. The platform is designed to support identification and prioritization of biological targets for follow-up. Each drug target is linked to a disease using integrated genome-wide data from a broad range of data sources. The platform provides either a target-centric workflow to identify diseases that may be associated with a specific target, or a disease-centric workflow to identify targets that may be associated with a specific disease. Users can easily transition between these target- and disease-centric workflows. The Open Targets Validation Platform is accessible at https://www.targetvalidation.org.

The melanoma-linked "redhead" MC1R influences dopaminergic neuron survival.

OBJECTIVE: Individuals with Parkinson disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson disease. Melanoma is strongly tied to red hair/fair skin, a phenotype of loss-of-function polymorphisms in the MC1R (melanocortin 1 receptor) gene. Loss-of-function variants of MC1R have also been linked to increased risk of Parkinson disease. The present study is to investigate the role of MC1R in dopaminergic neurons in vivo. METHODS: Genetic and pharmacological approaches were employed to manipulate MC1R, and nigrostriatal dopaminergic integrity was determined by comprehensive behavioral, neurochemical, and neuropathological measures. RESULTS: MC1Re/e mice, which carry an inactivating mutation of MC1R and mimic the human redhead phenotype, have compromised nigrostriatal dopaminergic neuronal integrity, and they are more susceptible to dopaminergic neuron toxins 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, a selective MC1R agonist protects against MPTP-induced dopaminergic neurotoxicity. INTERPRETATION: Our findings reveal a protective role of MC1R in the nigrostriatal dopaminergic system, and they provide a rationale for MC1R as a potential therapeutic target for Parkinson disease. Together with its established role in melanoma, MC1R may represent a common pathogenic pathway for melanoma and Parkinson disease. Ann Neurol 2017;81:395-406.

The Missing Link: Connection Is the Key to Resilience in Medical Education.

Awareness of the risks of burnout, depression, learner mistreatment, and suboptimal learning environments is increasing in academic medicine. A growing wellness and resilience movement has emerged in response to these disturbing trends; however, efforts to address threats to physician resilience have often emphasized strategies to improve life outside of work, with less attention paid to the role of belonging and connection at work. In this Commentary the authors propose that connection to colleagues, patients, and profession is fundamental to medical learners' resilience, highlighting "social resilience" as a key factor in overall well-being. They outline three specific forces that drive disconnection in medical education: the impact of shift work, the impact of the electronic medical record, and the impact of "work-life balance." Finally, the authors propose ways to overcome these forces in order to build meaningful connection and enhanced resilience in a new era of medicine.

Systematic Review and Meta-Analysis on the Influence of Surgeon Specialization on Outcomes Following Appendicectomy in Children.

The aim of this study is to assess the influence of surgeon specialization on outcomes following appendicectomy in children.General surgeons and pediatric surgeons manage appendicitis in children; however, the influence of subspecialization on outcomes remains unclear.Two authors searched Medline and Embase to identify relevant studies. Eligible studies were comparative and provided data on children who had appendicectomy while under the care of general or pediatric surgical teams. Two authors initially screened titles and abstracts and then full text manuscripts were evaluated. Data were extracted by 2 authors using an electronic spreadsheet. Pooled risk ratios and pooled mean differences were used in analyses.We identified 9 relevant studies involving 50,963 children who were managed by general surgery teams and 15,032 children who were managed by pediatric surgery teams. A normal appendix was removed in 4660/48,105 children treated by general surgery units and in 889/14,760 children treated by pediatric units (pooled risk ratio 1.79; 95% confidence interval [CI] 1.26-2.54; P = 0.001). Children managed in general units had shorter mean hospital stays compared with children managed in pediatric units (pooled mean difference -0.70 days; 95%CI -1.09 to -0.30; P = 0.0005). There were no significant differences regarding wound infections, intra-abdominal abscesses, readmissions, or mortality.We found that children who were managed by specialized pediatric surgery teams had lower rates of negative appendicectomy although mean length of stay was longer. Our article is based upon a group of heterogeneous and mostly retrospective studies and therefore there is little external validity. Further studies are needed.

Cardiotoxicity and cardioprotection in childhood cancer.

Children diagnosed with cancer are now living longer as a result of advances in treatment. However, some commonly used anticancer drugs, although effective in curing cancer, can also cause adverse late effects. The cardiotoxic effects of anthracycline chemotherapy, such as doxorubicin, and radiation can cause persistent and progressive cardiovascular damage, emphasizing a need for effective prevention and treatment to reduce or avoid cardiotoxicity. Examples of risk factors for cardiotoxicity in children include higher anthracycline cumulative dose, higher dose of radiation, younger age at diagnosis, female sex, trisomy 21 and black race. However, not all who are exposed to toxic treatments experience cardiotoxicity, suggesting the possibility of a genetic predisposition. Cardioprotective strategies under investigation include the use of dexrazoxane, which provides short- and long-term cardioprotection in children treated with doxorubicin without interfering with oncological efficacy, the use of less toxic anthracycline derivatives and nutritional supplements. Evidence-based monitoring and screening are needed to identify early signs of cardiotoxicity that have been validated as surrogates of subsequent clinically significant cardiovascular disease before the occurrence of cardiac damage, in patients who may be at higher risk.

Anatomy and bronchoscopy of the porcine lung. A model for translational respiratory medicine.

The porcine model has contributed significantly to biomedical research over many decades. The similar size and anatomy of pig and human organs make this model particularly beneficial for translational research in areas such as medical device development, therapeutics and xenotransplantation. In recent years, a major limitation with the porcine model was overcome with the successful generation of gene-targeted pigs and the publication of the pig genome. As a result, the role of this model is likely to become even more important. For the respiratory medicine field, the similarities between pig and human lungs give the porcine model particular potential for advancing translational medicine. An increasing number of lung conditions are being studied and modeled in the pig. Genetically modified porcine models of cystic fibrosis have been generated that, unlike mouse models, develop lung disease similar to human cystic fibrosis. However, the scientific literature relating specifically to porcine lung anatomy and airway histology is limited and is largely restricted to veterinary literature and textbooks. Furthermore, methods for in vivo lung procedures in the pig are rarely described. The aims of this review are to collate the disparate literature on porcine lung anatomy, histology, and microbiology; to provide a comparison with the human lung; and to describe appropriate bronchoscopy procedures for the pig lungs to aid clinical researchers working in the area of translational respiratory medicine using the porcine model.

Pseudomonas aeruginosa PA1006 is a persulfide-modified protein that is critical for molybdenum homeostasis.

A companion manuscript revealed that deletion of the Pseudomonas aeruginosa (Pae) PA1006 gene caused pleiotropic defects in metabolism including a loss of all nitrate reductase activities, biofilm maturation, and virulence. Herein, several complementary approaches indicate that PA1006 protein serves as a persulfide-modified protein that is critical for molybdenum homeostasis in Pae. Mutation of a highly conserved Cys22 to Ala or Ser resulted in a loss of PA1006 activity. Yeast-two-hybrid and a green-fluorescent protein fragment complementation assay (GFP-PFCA) in Pae itself revealed that PA1006 interacts with Pae PA3667/CsdA and PA3814/IscS Cys desulfurase enzymes. Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) "top-down" analysis of PA1006 purified from Pae revealed that conserved Cys22 is post-translationally modified in vivo in the form a persulfide. Inductively-coupled-plasma (ICP)-MS analysis of ΔPA1006 mutant extracts revealed that the mutant cells contain significantly reduced levels of molybdenum compared to wild-type. GFP-PFCA also revealed that PA1006 interacts with several molybdenum cofactor (MoCo) biosynthesis proteins as well as nitrate reductase maturation factor NarJ and component NarH. These data indicate that a loss of PA1006 protein's persulfide sulfur and a reduced availability of molybdenum contribute to the phenotype of a ΔPA1006 mutant.

DbVar and DGVa: public archives for genomic structural variation.

Much has changed in the last two years at DGVa (http://www.ebi.ac.uk/dgva) and dbVar (http://www.ncbi.nlm.nih.gov/dbvar). We are now processing direct submissions rather than only curating data from the literature and our joint study catalog includes data from over 100 studies in 11 organisms. Studies from human dominate with data from control and case populations, tumor samples as well as three large curated studies derived from multiple sources. During the processing of these data, we have made improvements to our data model, submission process and data representation. Additionally, we have made significant improvements in providing access to these data via web and FTP interfaces.